Protein kinases are key regulators of essential cellular processes, and because they contain a distinct active site, thereby allowing compound binding, kinases are an attractive area for anti-cancer drug discovery [1]. However, it was not until the successful clinical development of imatinib, targeting BCR-ABL, that the first targeted protein kinase inhibitor became an approved cancer chemotherapeutic [2]. Currently protein kinases are a very active area for cancer drug discovery with many protein kinase families being the focus of drug development programs. Such discovery programs often target signalling pathways that become deregulated during tumour development.
Members of the ErbB family, like many other growth factor receptors, dimerise upon ligand stimulation and undergo autophosphorylation through their cytoplasmic tyrosine kinase domains. Once activated, the ErbB kinases transduce their signals via a number of cellular protein kinases, including ERK and PKB, to ultimately result in upregulation of Cyclin D1 levels leading to activation of cyclin dependent kinases (CDKs) and the initiation of cellular proliferation [3]. Over-stimulation of ErbB receptor tyrosine kinase signalling has been documented in a number of different human cancers, including overexpression of HER2 (ErbB2) in up to 30% of breast cancer patients [4], while EGFR (ErbB1) is overexpressed in ovarian carcinomas (35-60%), head and neck tumours (70-100%) and non-small cell lung cancer (NSCLC; 50-90%) [5, 6]. Two main approaches have been pursued for the development of drugs that target the ErbB family. Humanised monoclonal antibodies such as trastuzumab and cetuximab bind to the HER2 and EGF receptors respectively, thereby blocking receptor dimerization/activation and facilitating removal of these proteins from the cell surface [3]. In contrast, erlotinib and gefitinib are small molecules that bind directly to the ATP-binding active site of the EGFR, blocking tyrosine kinase activity [7]. For each of these agents, the subsequent loss of mitogenic signalling results in the cessation of cellular proliferation.
The CDKs are a second kinase family that have attracted a considerable amount of interest from a drug discovery perspective; with the three most advanced compounds, seliciclib (CYC202, R-roscovitine), alvocidib (flavopiridol) and SNS-032 (formerly BMS-387032) all currently in Phase II clinical development [8, 9]. Through their key role of phosphorylating proteins involved in the regulation of cell cycle checkpoints, CDKs control the orderly progression of the cell division cycle [8]. In cancer cells activation of CDKs by either overexpression of their cognate partners, the cyclins, or loss of the endogenous inhibitors such as p16 leads to inappropriate proliferation of cells that would normally be arrested and either repaired or induced to undergo apoptosis at specific cell cycle checkpoints [10]. In addition to controlling the cell cycle, some CDKs, such as CDK7 and CDK9, regulate transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Seliciclib, alvocidib and SNS-032 all inhibit CDK7 and/or 9 thereby leading to the inhibition of transcription, and downregulation of proteins such as Mcl-1 and cyclin D1 [11, 12], which have short half-lives of approximately 3 h and 30 min respectively [13, 14].
The present invention seeks to provide new combinations that have therapeutic applications in the treatment of a range of proliferative disorders, more particularly cancer.